Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic ras is a dominant predictor for resistance

Nathan T. Ihle, Robert Lemos, Peter Wipf, Adly Yacoub, Clint Mitchell, Doris Siwak, Gordon Mills, Paul Dent, D. Lynn Kirkpatrick, Garth Powis

Research output: Contribution to journalArticle

228 Citations (Scopus)

Abstract

The novel phosphatidylinositol-3-kinase (PI3K) inhibitor PX-866 was tested against 13 experimental human tumor xenografts derived fromcell lines of various tissue origins. Mutant PI3K (PIK3CA) and loss of PTEN activity were sufficient, but not necessary, as predictors of sensitivity to the antitumor activity of the PI3K inhibitor PX-866 in the presence of wild-type Ras, whereas mutant oncogenic Ras was a dominant determinant of resistance, even in tumors with coexisting mutations in PIK3CA. The level of activation of PI3K signaling measured by tumor phosphorylated Ser473-Akt was insufficient to predict in vivo antitumor response to PX-866. Reverse-phase protein array revealed that the Ras-dependent downstream targets c-Myc and cyclin B were elevated in cell lines resistant to PX-866 in vivo. Studies using an H-Ras construct to constitutively and preferentially activate the three best-defined downstream targets of Ras, i.e., Raf, RalGDS, and PI3K, showed that mutant Ras mediates resistance through its ability to use multiple pathways for tumorigenesis. The identification of Ras and downstream signaling pathways driving resistance to PI3K inhibition might serve as an important guide for patient selection as inhibitors enter clinical trials and for the development of rational combinations with other molecularly targeted agents.

Original languageEnglish (US)
Pages (from-to)143-150
Number of pages8
JournalCancer Research
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Mutation
Cyclin B
Neoplasms
Protein Array Analysis
Heterografts
Patient Selection
PX-866
Carcinogenesis
Clinical Trials
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic ras is a dominant predictor for resistance. / Ihle, Nathan T.; Lemos, Robert; Wipf, Peter; Yacoub, Adly; Mitchell, Clint; Siwak, Doris; Mills, Gordon; Dent, Paul; Kirkpatrick, D. Lynn; Powis, Garth.

In: Cancer Research, Vol. 69, No. 1, 01.01.2009, p. 143-150.

Research output: Contribution to journalArticle

Ihle, Nathan T. ; Lemos, Robert ; Wipf, Peter ; Yacoub, Adly ; Mitchell, Clint ; Siwak, Doris ; Mills, Gordon ; Dent, Paul ; Kirkpatrick, D. Lynn ; Powis, Garth. / Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic ras is a dominant predictor for resistance. In: Cancer Research. 2009 ; Vol. 69, No. 1. pp. 143-150.
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